ORGANIC LETTERS
Enantioselective Route to 5-Methyl- and 5,7-Dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine: Secondary Amines with Switchable Axial Chirality
2009 Vol. 11, No. 7 1663-1666
Silvain L. Pira,† Timothy W. Wallace,*,† and Jonathan P. Graham‡ School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K., and GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SteVenage, Herts SG1 2NY, U.K.
[email protected] Received February 15, 2009
ABSTRACT
(-)-5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared enantioselectively from 2′-acetylbiphenyl-2-carboxylic acid, using (R)-2-phenylglycinol as an auxiliary for the control of both elements of chirality. The biaryl axis in 4 preferentially adopts the aS-configuration, with the methyl substituent pseudoequatorial, but conversion into the corresponding N-Boc derivative locks the axis into the aR-configuration, as predicted on the basis of molecular mechanics calculations.
The conformational properties of a three-atom bridged biaryl of the form 1 equip such a unit with the axis-center stereochemical relay that is the key structural component in many catalytic enantioselective processes. This relay is exemplified by the metal-coordinated BINAP 2, in which the spatial arrangement of the diphenylphosphine groups in the region of the metal atom depends on the configuration of the biaryl axis.1 The same type of axis-center relay is present in colchicine 3, and its operation has an important bearing on the ability of this alkaloid and its analogues to bind to tubulin and thereby act as cytotoxic agents.2 Our interest in the mechanics and reversibility of this type of stereochemical relay led us to select 5-methyl-6,7-dihydro5H-dibenz[c,e]azepine 4, the simplest axis-center combination, for a detailed study. Simple models of 4 demonstrate †
The University of Manchester. GlaxoSmithKline. (1) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (2) (a) Brossi, A. J. Med. Chem. 1990, 33, 2311. (b) For a correction, see: Berg, U.; Bladh, H. HelV. Chim. Acta 1999, 82, 323. ‡
10.1021/ol900333c CCC: $40.75 Published on Web 03/10/2009
2009 American Chemical Society
the mechanics of the coupling between the configurations of C(5) and the biaryl axis and show that the pseudoequatorial orientation of a 5R-substituent in the azepine ring demands an S-configured biaryl axis and vice versa (Scheme 1). By analogy with colchicine 3, it might be anticipated that the amine (5R)-4 would exist predominantly in the aSconfiguration, although this type of equilibrium can be finely balanced.2a,3 Derivatives 5 of 6,7-dihydro-5H-dibenz[c,e]azepine have become prominent in applications of conformationally flex-
Scheme 1. Conformational Equilibrium in 5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4
ible (tropos) biaryl units in various structural roles.4 There is a relatively low barrier to axis inversion in such units (a value for ∆Gq of 56 kJ/mol for the inversion barrier in the N,N-dimethylammonium bromide was estimated from NMR data5), and the axial configuration is sensitive to central chirality in the R-group.6 Studies into the use of homochiral amines as reagents, catalysts, and ligands have also featured fixed-axis dinaphthazepines such as 67 and 7.8 In contrast, 6,7-dihydro-5H-dibenz[c,e]azepines bearing substituents at C(5) and/or C(7) are surprisingly rare, and the monoalkylated (3) (a) Brossi, A.; Boye´, O.; Muzaffar, A.; Yeh, H. J. C.; Toome, V.; Wegrzynski, B.; George, C. FEBS Lett. 1990, 262, 5. (b) For a pertinent discussion, see: Cavazza, M.; Zandomeneghi, M.; Pietra, F. Tetrahedron Lett. 2000, 41, 9129. (4) For discussions and examples, see: (a) Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, 1561. (b) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929. (c) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551. (d) Vial, L.; Lacour, J. Org. Lett. 2002, 4, 3939. (e) Vasse, J.-L.; Stranne, R.; Zalubovskis, R.; Gayet, C.; Moberg, C. J. Org. Chem. 2003, 68, 3258. (f) Mikami, K.; Yamanaka, M. Chem. ReV. 2003, 103, 3369. (g) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. (h) Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C. Tetrahedron 2004, 60, 8801. (i) Vachon, J.; Lauper, C.; Ditrich, K.; Lacour, J. Tetrahedron: Asymmetry 2006, 17, 2334. (j) Aillaud, I.; Wright, K.; Collin, J.; Schulz, E.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2008, 19, 82. (5) Sutherland, I. O.; Ramsay, M. V. J. Tetrahedron 1965, 21, 3401. (6) (a) Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita, A.; Rosini, C. J. Am. Chem. Soc. 2006, 128, 6893. (b) Dutot, L.; Wright, K.; Wakselman, M.; Mazaleyrat, J.-P.; Peggion, C.; De Zotti, M.; Formaggio, F.; Toniolo, C. Tetrahedron Lett. 2008, 49, 3475. (c) See also: Tichy, M.; Gunterova, J.; Zavada, J. Collect. Czech. Chem. Commun. 1997, 62, 1080. (7) For examples and leading references, see: (a) Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. J. Org. Chem. 1985, 50, 3916. (b) Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1992, 57, 2114. (c) Rosini, C.; Tanturli, R.; Pertici, P.; Salvadori, P. Tetrahedron: Asymmetry 1996, 7, 2971. (d) Mazaleyrat, J.-P. Tetrahedron: Asymmetry 1997, 8, 2709. (e) Widhalm, M.; Nettekoven, U.; Mereiter, K. Tetrahedron: Asymmetry 1999, 10, 4369. (f) Stranne, R.; Vasse, J.-L.; Moberg, C. Org. Lett. 2001, 3, 2525. (g) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. (h) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Tetrahedron 2006, 62, 11425. (i) Eberhardt, L.; Armspach, D.; Matt, D.; Toupet, L.; Oswald, B. Eur. J. Org. Chem. 2007, 5395. (j) Shibatomi, K.; Tsuzuki, Y.; Nakata, S.; Sumikawa, Y.; Iwasa, S. Synlett 2007, 551. (k) Vishnumaya; Singh, V. K. Org. Lett. 2007, 9, 1117. (l) Zalubovskis, R.; Bouet, A.; Fjellander, E.; Constant, S.; Linder, D.; Fischer, A.; Lacour, J.; Privalov, T.; Moberg, C. J. Am. Chem. Soc. 2008, 130, 1845. (m) Li, X.-J.; Zhang, G.-W.; Wang, L.; Hua, M.-Q.; Ma, J.-A. Synlett 2008, 1255. (n) Mazaleyrat, J.-P.; Wright, K. Tetrahedron Lett. 2008, 49, 4537. (8) (a) Meyers, A. I.; Nguyen, T. H. Tetrahedron Lett. 1995, 36, 5873. (b) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996, 61, 1194. (c) Bourghida, M.; Widhalm, M. Tetrahedron: Asymmetry 1998, 9, 1073. (d) Pisani, L.; Superchi, S. Tetrahedron: Asymmetry 2008, 19, 1784. (9) It is reported (Chem. Abstr. 1988, 108, 625) that the amine (()-4 was prepared, together with several homologues, in the course of a study into the control of hyperlipidemia: Hall, I. H.; Wyrick, S. D.; Chapman, J. M. U.S. 4689326, 1987. However, the preparative procedure and the NMR data provided in this publication indicate that the compounds prepared were the symmetrical N-alkyl isomers. 1664
series that starts with 4 is unknown.9 However, the dimethyl homologues 8 and 9 have been prepared by Ku¨ndig and coworkers,10 who identified the lithium amide derived from 8 as an enantioselective base with some promise,11 while more recently the preparation of the highly oxygenated derivative 10 was described by Baudoin and co-workers.12 The published routes to 8 and 10 both involve the late formation of the Ar-Ar bond using Pd-catalyzed triflate-stannane (Stille)10 or halide-boronate (Suzuki-Miyaura)12 coupling protocols, respectively. We herein provide the details of an alternative approach to such compounds in which the axiscenter stereochemical relay in the three-atom bridged biaryl is exploited at the outset, using a chiral auxiliary strategy, and in subsequent steps so as to provide (5R)-4 and (5R,7R)-8 in a concise and stereocontrolled sequence.
Our route to (5R)-4 begins with the condensation of the biphenylcarboxylic acid 11, prepared from diphenic anhydride in two steps by slight modifications of the published procedures,13 with (R)-2-phenylglycinol 12 under the conditions developed by ourselves14 and, independently, Levacher’s group,15 which provides the oxazolidine lactam 1315 diastereoselectively and in good yield (Scheme 2). Lactams such as these are remarkably resistant to the formation of acyliminiums,14b and 13 proved stable to various reduction protocols that would normally involve such intermediates (Et3SiH/TFA, etc.). However, lactams are susceptible to hydroborating agents,16 and treating 13 with borane-methyl sulfide gave a mixture of two reduction products that were identified from spectroscopic data as the isomeric amines 15 and 16. It seemed likely that carbonyl and oxazolidine reduction had proceeded sequentially but that the stereoselectivity of the second reduction step was poor. This was remedied by reference to the pioneering work of the Meyers group, who observed that alane often provided high diastereoselectivity in this type of reduction.17 Accordingly, the treatment of 13 with 4.7 equiv of alane gave a high yield of one of the two amines observed previously, and this was (10) Saudan, L. A.; Bernardinelli, G.; Ku¨ndig, E. P. Synlett 2000, 483. (11) Pache, S.; Botuha, C.; Franz, R.; Ku¨ndig, E. P.; Einhorn, J. HelV. Chim. Acta 2000, 83, 2436. (12) (a) Joncour, A.; De´cor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O. Angew. Chem., Int. Ed. 2006, 45, 4149. (b) Joncour, A.; De´cor, A.; Liu, J.-M.; Tran Huu Dau, M.-E.; Baudoin, O. Chem. Eur. J. 2007, 13, 5450. (13) Ried, W.; Conte, R. Chem. Ber. 1971, 104, 1573. (14) (a) Edwards, D. J.; Pritchard, R. G.; Wallace, T. W. Tetrahedron Lett. 2003, 44, 4665. (b) Edwards, D. J.; House, D.; Sheldrake, H. M.; Stone, S. J.; Wallace, T. W. Org. Biomol. Chem. 2007, 5, 2658. (15) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517. (16) (a) Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912. (b) Brown, H. C.; Nazer, B.; Cha, J. S.; Sikorski, J. A. J. Org. Chem. 1986, 51, 5264. (c) Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett. 1999, 40, 3673. Org. Lett., Vol. 11, No. 7, 2009
Scheme 2. Enantioselective Route to 4 from the Lactam 13a
19 [δH (500 MHz, CDCl3) 1.54 (9 H, s, OCMe3), 0.89 (6 H, d, J ) 7.0 Hz, 5-Me)] (Scheme 3). The product mixture also
Scheme 3. Diastereoselective Methylation of 4 To Obtain 8
a For clarity, the hydrogen atoms are omitted from the X-ray crystal structure of the quaternary salt 17.
characterized as the expected retention product 15 by X-ray crystallographic analysis of the derived quaternary ammonium salt 17, mp 156-157 °C (MeOH). Reductive cleavage of the chiral auxiliary from 15 via catalytic hydrogenation cleanly provided the target amine (-)-4 (94%) as a pale yellow oil, [R]25D -23.5 ( 1 (c 0.65, CHCl3), δH (500 MHz, CDCl3) 1.50 (3 H, d, J ) 6.6 Hz, 5-Me). With the amine 4 in hand, we sought to introduce a second methyl group at C(7) and thereby gain access to the 5,7dimethyl series that includes Ku¨ndig’s amine 8. The lithiation-based methodology developed for the R-alkylation of nitrogen heterocycles18 holds out the prospect of diastereoselectivity, and conversion of the fixed-axis dinaphthazepine 6 into the trans-5,7-dimethyl analogue 7 can be achieved through the use of amidine or nitroso activation.8 However, it was not known how a flexible biaryl such as 4 might respond to these protocols, and neither of them is particularly convenient. In the event, treating the Boc derivative 18, prepared from 4 in the usual way, with 6 equiv of secbutyllithium at -78 °C, followed by iodomethane, gave a mixture of products dominated by the trans-dimethyl system (17) (a) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656. (b) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413. (18) (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (b) Meyers, A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652. (c) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552, and references cited therein. Org. Lett., Vol. 11, No. 7, 2009
contained a significant quantity of the gem-dimethyl isomer 20 [δH (500 MHz, CDCl3) 1.65 (6 H, br s, 2 × 5-Me), 1.51 (9 H, s, CMe3)], and on the basis of limited data it is speculated that only a small amount of the meso-diastereoisomer 21 [δH (300 MHz, CDCl3) 4.90 (1 H, q, J ) 7.0 Hz, 5-H or 7-H), 1.38 (3 H, d, J ) 7.0 Hz, 5-Meeq or 7-Meeq)] was among the reaction products. Several attempts to optimize the yield of 19 were thwarted by poor conversion which we attributed to aggregation phenomena, but the use of Schlosser’s “LIDAKOR” base19 provided 19 in 87% yield after chromatography. The removal of the Boc group from 19 using aqueous phosphoric acid20 gave the amine (-)-8, [R]25D -81 ( 4 (c 0.61, CH2Cl2) {lit.10 [R]20D -83.1 (c 0.61, CH2Cl2)}. The properties of the intermediates prepared en route to 4 and 8, when compared to those of the amines themselves, offer further insight into the mechanics and potential of the axis-center stereochemical relay in 6,7-dihydro-5H-dibenz[c,e]azepines. The conformation of the seven-membered ring can generally be deduced via 1H NMR spectroscopy, a pseudoaxial methyl group at C(5) or C(7) experiencing a marked upfield shift due to the effects of the distal aromatic ring.8,10,21 On this basis it can be seen that the conversion of the amine (-)-4 (δMe 1.50 ppm) into the Boc derivative (+)-18 (δMe 0.86 ppm) is accompanied by a change in the orientation of the methyl group from pseudoequatorial to (19) Mordini, A.; Ben Rayana, E.; Margot, C.; Schlosser, M. Tetrahedron 1990, 22, 2401. (b) Takagishi, S.; Schlosser, M. Synlett 1991, 119. (20) Li, B.; Berliner, M.; Buzon, R.; Chiu, C. K.-F.; Colgan, S. T.; Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman, K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.; Weaver, J.; Zhang, Z.; Zhang, Z. J. Org. Chem. 2006, 71, 9045. (21) For examples in the analogous phosphepine series, see Kasa´k, P.; Mereiter, K.; Widhalm, M. Tetrahedron: Asymmetry 2005, 16, 3416. 1665
pseudoaxial. The mechanics of the axis-center relay (Scheme 1) require that this change be accompanied by the inversion of the biaryl axis, as can be inferred from the change in sign of the specific rotation,22 so it is demonstrated that the axial configuration of a 5-substituted amine such as 4 can be “switched” by modification of the nitrogen substituent. The preference of 18 for the (aR)-configuration is a natural consequence of the steric interaction between the 5-methyl and Boc groups, which is accentuated by the trigonalisation of the nitrogen atom and mirrors the behavior of other Bocsubstituted nitrogen heterocycles.18 To gain a more quantitative view of this phenomenon, various alkyl-substituted 6,7dihydro-5H-dibenz[c,e]azepine derivatives were modeled using molecular mechanics techniques (Table 1).
Table 1. Calculated Differences in Steric Energy (kJ mol-1) of the aS and aR Conformational Minima of Various 6,7-Dihydro-5H-dibenz[c,e]azepine Derivatives (Macromodel 8.0, MM3)
4 8 22 23 24 25 26 27 28 29 30 31 32
R1
R2
R3
R4
∆Ea
ratiob
Me Me Et Pri But Me Me Me Me Me Me Me Me
H Me H H H H Me H Me H Me H Me
H H H H H Me Me CHO CHO COMe COMe CO2Me CO2Me
H H H H H Me Me H H H H H H
4.4 11.2 3.7 0.5 -2.0 -8.2 -14.9 -11.4 -26.9 -18.9 -38.6 -19.2 -37.9
86:14 99:1 82:18 55:45 31:69 4:96 0.2:99.8 1:99 0:100 0:100 0:100 0:100 0:100
a Calculated difference in steric energy EaR - EaS (kJ mol-1) of the respective global conformational minima in the aR and aS manifolds. b The ratio aS:aR at 298 K assuming dynamic equilibrium.
The modeling results are consistent with the observed preference of (5R)-4 and (5R,7R)-8 for the aS-configuration but suggest that N-acylation23 will invert and effectively “lock” the biaryl axis of this type of amine. The preference of the 5-alkyl substituent for a pseudoequatorial orientation (22) Fitts, D. D.; Siegel, M.; Mislow, K. J. Am. Chem. Soc. 1958, 80, 480. (23) The 1H NMR chemical shift of the 5-methyl substituent in the tertiary amine 15 (δH 0.92) is consistent with a pseudoaxial orientation, and therefore an aR-configuration for this compound, indicating that the conformation of the amine 4 can also be modified by N-alkylation.
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decreases as its steric bulk increases and its interaction with H(4) becomes more significant, with the isopropyl system 23 being close to the crossover point. The proposal, made by Ku¨ndig et al.,10 that substitution at H(4) and H(8) of 8 should increase the preference of the 5- and 7-methyl groups for pseudoaxial orientations and thereby exaggerate the C2symmetric environment around the nitrogen atom is supported by the results for 25 and 26, suggesting that the lithium amides derived from these amines may be more effective than 8 as mediators of enantioselective deprotonation. Finally, the detailed mechanism of the trans-selective methylation of 18 to give 19 is unclear, but from the overwhelming preference of the model carbamate 31 for the aR-configuration, it can be inferred that, for the substrate 18, the pro-R location of C(7) will be pseudoaxial and therefore the more exposed, kinetically reactive site throughout the reaction sequence. In conclusion, we have prepared (R)-5-methyl-6,7-dihydro5H-dibenz[c,e]azepine (-)-4, the first of a new series of secondary amines incorporating an axis-center stereochemical relay, from 2′-acetylbiphenyl-2-carboxylic acid using an auxiliary strategy for the simultaneous control of both elements of chirality. The amine (-)-4 can be stereoselectively methylated to obtain the known (R,R)-5,7-dimethyl homologue (-)-8 in three steps. The stereochemical relay in the amine 4 effectively extends to the nitrogen atom, where acylation has the effect of forcing the 5-methyl substituent into a pseudoaxial orientation, thereby inverting and locking the configuration of the biaryl axis. The mechanics of this type of relay may be useful for controlling the stereochemistry of functionalized biaryls, notably those with 2-arylpyridine or 2,2′-bipyridyl cores, or as a component of molecular devices. We also anticipate that other types of bonding or coordination at nitrogen will elicit a quantifiable response in amines with this relay, which may therefore have analytical applications. These various possibilities are currently under investigation. Acknowledgment. We are grateful to the EPSRC and GlaxoSmithKline for their financial support of this work, and we warmly thank Dr. Robin Pritchard (University of Manchester) for the X-ray analysis and Mrs. Val Boote (University of Manchester) for MS measurements. We also wish to acknowledge the use of the EPSRC’s Chemical Database Service at Daresbury.24 Supporting Information Available: Experimental procedures and characterization of compounds, X-ray data, 1H and 13C NMR spectra, and structures generated via molecular mechanics calculations. This material is available free of charge via the Internet at http://pubs.acs.org. OL900333C (24) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36, 746.
Org. Lett., Vol. 11, No. 7, 2009
